The physiological mechanisms that produce satiety after food intake have not yet been defined. Several peptides normally secreted from the gastrointestinal tract during eating have been shown to suppress food intake if given before meals (Smith, G. P. and J. Gibbs. In: Martin J B, et al. cds. Neurosecretion and brain peptides. New York: Raven, 389–395 (1981): Gibbs J. and Smith G. P. Fed. Proc. 45:1391–1395 (1986); Gibbs J. and Smith G. P. Ann. N.Y. Acad. Sci. 547:210–216 (1988)). During recent years, the role of the preabsorptive release of gut peptides (especially cholecystokinin, bombesin-like peptides and glucagon-like peptides) in the production of meal-ending satiety has been extensively investigated in animals (Gibbs J. and Smith G. P. (1988): Gibbs J. et al. J. Comp. Physiol. Psychol. 84:488–495 (1973); Bado A. et al., Pharmacol. Biochem. Behav. 31:297–303 (1988); Weller A. et al. Science, 247:1589–1591 (1989); Silver A. J. et al., Am. J. Physiol., 256:R646 R652 (1989); Turton M. D. et al., Nature 379:69–72, (1996)). Cholecystokinin (CCK) and bombesin-like peptides have also been studied in humans (Lieverse R. J. et al., Gastroenterology 106: 1451–1454 (1994); Gutzwiller J. P. et al., Gastroenterology 106: 1168–1173 (1994)). CCK, the first gut peptide proposed to act as a satiety signal (Gutzwiller, J. P. (1994)), has received the major share of interest in human studies reported in the literature.
Glucagon-like peptide-1 (7–36) amide (GLP-1), the biologically active form of the GLP-1 protein resulting from a post-translational modification of the prohormone proglucagon, is released from enteroendocrine cells from the distal gut in response to food intake. GLP-1 has been shown to reduce food intake in rats when administered intracerebroventricularly, whereas intraperitoneal application of the peptide did not have any effect (Turton M. D. et al., Nature 379:69–72, (1996)). Further, when a GLP-1 receptor-specific antagonist was infused intracerebroventricularly, it blocked endogenous peptide, and thus affected only physiologically active circuits. Blocking endogenous GLP-1 causes healthy, already satiated animals to eat more. Turton and co-workers have, therefore, suggested that intracerebroventicular GLP-1 inhibits feeding in fasted rats (Turton, et al. (1996)). Others have reported no effect on appetite from the infusion of GLP-1 over 210 minutes in obese humans, thereby having discouraged further investigation of GLP-1 in human appetite suppression. These inconsistent studies have discouraged further investigation of GLP-1 for humans.
In animals, expression of GLP-1 receptors has been found in the hypothalamus, the brainstem and in the periventricular area, but not in the cortex. GLP-1 receptors were found in the endocrine pancreas (Hörsch. D. et al. Pancreas 14(3):290–294 (1997)), the adipose tissue (Valverde I. et al., Endocrinology 132:75–79 (1993)) and the stomach (Uttenthal, L. O. and Blazquez, E. FEBS Lett; 262:139–141 (1990); Schmidtler J. et al., Am. J. Physiol. 267:G423–G432 (1994)); and nerves containing GLP-1 have been identified in the brain (Jine S. L. C. et al., J. Comp. Neurol. 271:519–532 (1988): Salazar I. and Vaillant C. Cell Tissue Res. 261:355–358 (1990)). Thus, the GLP-1 receptor is present at sites where administration of exogenous GLP-1 appears to cause satiety; however, whether it is a satiety factor has not been confirmed. Injection of GLP-1 into the cerebral ventricles of fasted rats inhibited feeding, and this effect was blocked by the GLP-1 receptor antagonist exendin (9–39). Also, administration of exendin (9–39) alone doubled food intake in satiated rats (Turton M. D. et al., Nature 379:69–72, (1996)).
Even though GLP-1, as demonstrated here, controls appetite in normal humans, the use of GLP-1 to control appetite in diabetics is surprising for several reasons: first, diabetics normally have hypoinsulinemia, which is a major appetite stimulant. Accordingly, there would be an expected major uncertainty whether GLP-1 could counteract this stimulation and deliver appetite control. Secondly, diabetics are characterized by having hyperglycemia, which in many causes a functional deterioration of the autonomous neural control systems for the GI tract, and in later stages causes structural damage to these systems. Accordingly, there would be an expected major uncertainty whether GLP-1 could have an appetite control function in such diabetics.
It is a primary objective of the present invention to suppress human appetite with GLP-1 or its biologically active analogues.
Another objective of the present invention is to combine GLP-1 or its biologically active analogues with a pharmaceutically acceptable carrier to provide an effective treatment composition for humans for use in appetite control, including in diabetics.
A yet further objective of the present invention is to provide a method, means and composition userful by humans to reduce the spontaneous urge for food intake without significant adverse side effect consequences to the person's metabolic balance.
The method and manner of accomplishing each of the above objectives, as well as others, will be apparent from the detailed description of the invention which follows.